Kafkas Univ Vet Fak Derg KafKas Universitesi veteriner faKUltesi Dergisi 23 (2): 227-232, 2017 JoUrnal Home-Page: http://vetdergi.kafkas.edu.tr Research Article DOI: 10.9775/kvfd.2016.16334 online sUbmission: http://vetdergikafkas.org Serum Leptin and Ghrelin Levels and Their Relationship with Serum Cortisol, Thyroid Hormones, Lipids, Homocysteine and Folic Acid in Dogs with Compulsive Tail Chasing Ebru YALCIN 1 Zeki YILMAZ 1 Yesim OZARDA 2 1 Department of Internal Medicine, Faculty of Veterinary Medicine, Uludag University, TR-16059 Bursa - TURKEY 2 Department of Biochemistry, Medical School, Uludag University, TR-16059 Bursa - TURKEY Article Code: KVFD-2016-16334 Received: 13.06.2016 Accepted: 30.08.2016 Published Online: 06.09.2016 Citation of This Article Yalcın E, Yilmaz Z, Ozarda Y: Serum leptin and ghrelin levels and their relationship with serum cortisol, thyroid hormones, lipids, homocysteine and folic acid in dogs with compulsive tail chasing. Kafkas Univ Vet Fak Derg, 23 (2): 227-232, 2017. DOI: 10.9775/kvfd.2016.16334 Abstract The aim of this study was to investigate serum leptin and ghrelin levels and their relations with circulating cortisol, thyroid hormones, lipids, homocysteine (Hcy) and folic acid in dogs with compulsive tail chasing (CTC). The material of this study consists of fifteen dogs with CTC and 15 healthy controls of various weights, breeds, ages of both sexes were enrolled in the study. CTC was diagnosed on the basis of the dog’s behavioral history, clinical signs, and results of other medical assessments. None of the dogs were considered to have concurrent medical disease that would account for CTC. Dogs with CTC had a higher leptin (8.3±0.9 ng/mL vs 1.7±0.2 ng/mL, P<0.001) and lower ghrelin levels (74±7 pg/mL vs 144±41 pg/mL, P<0.05) than those of healthy controls. Serum cortisol, lipids (cholesterol, phospholipids and NEFA) and Hcy levels increased (P<0.05), whereas serum folic acid decreased (P<0.001) in dogs with CTC as compared with controls. Serum ghrelin correlated negatively with cholesterol (P<0.05), but serum leptin correlated positively with cholesterol, fT4, and phospholipids (P<0.05). These results suggest that serum leptin and ghrelin levels may bring up a new perspective on our understanding of the pathophysiological mechanisms associated with CTC. Serum levels of both hormones may be associated with serum levels of lipids and free T4. Keywords: Leptin, Ghrelin, Thyroid hormones, Lipids, Tail chasing, Dog Kompulsif Kuyruk Isıran Köpeklerin Serum Leptin ve Ghrelin Seviyeleri ve Serum Kortizol, Tiroid Hormonları, Lipidler, Homosistein ve Folik Asit İle İlişkileri Özet Bu çalışmanın amacı, kompulsif kuyruk ısıran köpeklerde serum leptin ve ghrelin seviyeleri ve sirküle eden kortizol, tiroid hormonları, lipidler, homosistein (Hcy) ve folik asit arasındaki ilişkiyi araştırmaktır. Çeşitli ağırlık, ırk, yaş ve her iki cinsiyetten 15 kuyruk ısıran ve kontrol grubu olarak 15 sağlıklı köpek çalışmaya dahil edildi. Kuyruk ısırma tanısı, davranış anamnez formu, klinik bulgular ve diğer medikal değerlendirmelerin sonuçlarına göre konuldu. Kompulsif kuyruk ısıran köpeklerin hiçbirinde eşlik eden başka bir medikal hastalık bulunmamaktaydı. Kompulsif kuyruk ısıran köpekler, kontrol grubundaki köpeklere göre yüksek leptin (8.3±0.9 ng/mL ve 1.7±0.2 ng/mL, P<0.001) ve düşük ghrelin (74±7 pg/mL ve 144±41 pg/mL, P<0.05) seviyesine sahipti. Kontrol grubu ile karşılaştırıldığında kompulsif kuyruk ısıran köpeklerin serum kortizol, lipid (kolesterol, fosfolipidler ve NEFA) ve Hcy seviyesi artmış (P<0.05), bunun aksine serum folik asid seviyesi (P<0.001) azalmıştır. Serum ghrelin seviyesi, kolesterol (P<0.05) ile negatif korelasyon gösterirken, serum leptin seviyesi, kolesterol, fT4 ve fosfolipidler (P<0.05) ile pozitif korelasyon göstermekteydi. Sonuçlar değerlendirildiğinde, serum leptin ve ghrelin seviyelerindeki değişikliklerin kompulsif kuyruk ısırmanın patofizyolojik mekanizmasını anlamak için yeni bir perspektif getireceği düşünülmektedir. Her iki hormon da serum lipid seviyeleri ve serbest T4 düzeyi ile ilişkili olabilir. Anahtar sözcükler: Leptin, Ghrelin, Tiroid hormonları, Lipidler, Kompulsif kuyruk ısırma, Köpek INTRODUCTION compulsive disorder includes excessive tail chasing, light/ shadow chasing and flank sucking [1-3]. Clinical and neuro- Obsessive compulsive disorder (OCD) is a neuro- biological similarities between dogs and humans with psychiatric disorder in humans and animals. Canine OCD were reported [3,4]. Thus, canine compulsive behaviors  İletişim (Correspondence)  +90 224 2940811, Fax: +90 224 2940873  yalcine@uludag.edu.tr 228 Serum Leptin and Ghrelin ... such as compulsive tail chasing (CTC) have been suggested the study as control after the consent of the owners and as a promising model for human OCD [3]. on the basis of normal physical examination results and complete blood count. Control dogs were of various Human and canine OCD have been associated with a weights (23.5±1.5 kg), mixed breeds of either sex (10 biochemical disturbance at the level of neurotransmitter males, 5 females), and ranged from 12-96 months (34±2.5 systems [1] and activation of hypothalamic-pituitary-adrenal months) in age. No significant differences were observed (HPA) system [5,6]. Compulsive disorders are also known to between the two groups regarding the aforementioned be stress responsive and compulsive symptoms increase parameters. The body condition score for each dog was at times of stress [6,7]. Serum cortisol level as an indicator of evaluated by using a 5-point scale (1: thin, 2: underweight, activated HPA system is used to describe the presence of 3: ideal, 4: overweight and 5: obese) [24]. All experiments stress in humans [8], dogs [9], and cats [10]. conducted by us in this study were performed in line with Leptin and ghrelin are two hormones related with ethical approval from the ethical committee of University energy balance. Leptin, an anorexigenic hormone, is a (16/1-5). mediator of long-term regulation of energy balance, Diagnostic Procedures suppressing food intake and thereby resulting in weight loss. Ghrelin, an orexigenic hormone, is playing a role in meal A behavioural diagnosis was made for each dog on initiation [11]. Recently, leptin and ghrelin hormones have the basis of the dog’s behavioural history, clinical signs, also been correlated in the pathophysiology of stress [12]. and results of other medical assessments, as published in Leptin inhibits and ghrelin facilitates neuroendocrine stress the previous studies [23,25]. Dogs were assessed for seizure responses in rats [12]. Hypercortisolemia increases serum disorder, opioid-mediated stereotypy, local vasculitis or levels of leptin and decreases serum levels of ghrelin in neuritis, anal sac diseases and pruritus. None of the dogs dogs. As serum levels of leptin and ghrelin are affected were considered to have concurrent medical disease (such by cortisol [13], it is possible to hypothesize that these as dermatological disease, vector–borne diseases, and renal hormones might play a role in the regulation of stress diseases) that would account for CTC. Behavioral history response in dogs with OCD. included age at onset, frequency and duration of bouts Current literature shows that some psychiatric disorders since onset, general history, and current or previous medical in humans might be related to the serum levels of folate conditions. All owners reported that their dogs commonly and homocysteine (Hcy) [14-16], lipids [17,18] and thyroid whined, barked, or growled during tail chasing. In this study, function [19]. Thyroid status is considered as an important affected dogs had to have tail chasing bouts for a minimum determinant of the serum level of total Hcy [20] and lipids of 60 s/bout at least 3 times/d during the previous two (cholesterol, lipoproteins, etc.) in humans [17,18,21,22]. There months in order to be included into the study. is also one study indicating a relationship between serum Sample Collection and Measurements level of lipid (serum cholesterol elevations) and OCD in dogs [23]. Based on the accumulated evidence, we hypo- Venous blood samples were collected, after a fasting thesized that circulating leptin, ghrelin, folate, Hcy, lipids period of 12-16 h, from cephalic veins into vacutainer tubes and thyroid hormones might have a role in dogs with OCD. with or without EDTA (Becton Dickinson, Temse, Belgium) Thus, in this study, to understand of pathophysiological for complete blood count (Cell Dyne 3500R, Abbott, mechanism of OCD, we investigated serum leptin and Germany) and serum biochemistry panel (Aeroset, Abbott), ghrelin levels and their relations with circulating thyroid respectively. All dogs were screened for common vector- hormones, folate, Hcy, lipids, and cortisol in dogs with CTC. borne diseases (anaplasmosis, borrelliosis, dirofilariosis, ehrlichiosis, and leishmaniosis) by speed tests (Bionote, MATERIAL and METHODS Anigen, South Korea), and dogs sero-positive for vector- borne pathogens were excluded from the study. Dogs Serum leptin and ghrelin levels were measured by This study was performed on 15 healthy dogs and radioimmunoassay (RIA) using a commercially available 15 dogs with CTC that were referred to the Small Animal kit (Multispecies leptin RIA kit and active ghrelin RIA kit, Clinics Internal Medicine Department, Faculty of Veterinary Linco Research, St. Charles, MO). Validity and reliability Medicine, Uludag University, Bursa, Turkey in January-July of these RIA kits for measuring serum leptin and ghrelin 2016. Dogs with CTC were 10-35 kg (mean 27.2 kg±1.5 levels in dog were determined in our previous studies [13,26]. kg), and of various breeds (3 Anatolian shepherd dogs, Since active ghrelin is too unstable to be measured in 3 German shepherd dogs, 3 Golden retrievers, 3 mixed stored samples [27] and acidification of plasma prevents breeds, 1 Terriers, 1 Doberman, 1 Labrador retriever), sex rapid desacylation of ghrelin [28], 1 N hydrogen chloride (11 males, 4 females) and age (8 months-9 years, mean was added to serum samples before freezing[13]. Serum 3.3±0.7 years) were evaluated. Dogs (n=15), which were cortisol was measured by a solid-phase chemiluminescent referred for vaccination purposes, were also enrolled in enzyme immunoassay system (Immulite 2000, BioDPC, Los 229 YALCIN, YILMAZ OZARDA Angees, CA) as reported earlier [26]. Table 1. Serum levels of leptin, ghrelin, lipids, thyroid hormones, homocysteine and folic acid in healthy dogs and dogs with compulsive tail Serum samples were tested for total thyroxin (T4), free T4 chasing (CTC) (fT4), triiodothyronine (T3), and free T3 (fT3) concentrations. CTC Healthy Controls Hormone analysis was performed by RIA techniques (Advia Parameters Mean±SEM Mean±SEM P Value CentaurTM) as reported earlier [29]. Leptin ng/mL 8.36±0.90 1.70±0.26 =<0.001 Serum total cholesterol, high-density lipoprotein Ghrelin pg/mL 74.94±7.29 144.11±41.41 = 0.029 cholesterol (HDL-C), very low-density lipoprotein cholesterol T. Cholesterol mg/dL 203.42±16.03 140.40±10.85 NS (VLDL-C) and triglycerides levels were measured by an HDL mg/dL 73.00±11.09 89.88±7.26 NS automated clinical chemistry analyzer (Architect ci8200; Abbott GmbH Co KG, Wiesbaden, Germany) using LDL mg/dL 128.11±11.99 32.44±3.25 =<0.001 commercially available assay kits (Abbott GmbH Co KG). VLDL mg/dL 15.94±1.87 12.50±1.28 NS Low-density lipoprotein cholesterol (LDL-C) concentrations Tg mg/dL 79.63±9.42 58.75±5.28 NS were calculated using the formula: Phospholipid mg/dL 338.16±17.05 276.11±14.60 =0.027 LDL-C(in milligrams per deciliter) = total cholesterol - Nefa mg/dL 1.74±0.17 0.85±0.15 =0.002 (HDL – C + triglyceride/5). TT4 µg/dL 1.79±0.09 1.91±0.14 NS fT ng/dL 0.72±0.10 0.48±0.02 =0.072 Serum non-esterified fatty acid (NEFA) concentration 4 was measured using a commercially available enzymatic TT3 ng/mL 0.44±0.03 0.34±0.03 NS colorimetric assay kit (Wako Chemicals, Neuss, Germany) [30]. fT3 pg/mL 1.87±0.15 1.34±0.10 =0.03 Serum phospholipids were measured by an enzymatic Hcy µmol/L 11.52±0.84 6.29±0.23 =<0.001 colorimetric method using a commercially available Folic acide ng/mL 3.25±0.32 6.41±0.56 =<0.001 assay kit (Wako Chemicals), which have been reported as choline-containing phospholipids (in milligrams per deciliter) [30]. (P<0.05) and serum leptin correlated positively with cholesterol, fT4, and phospholipids (P<0.05). There was a Statistical Analysis negative correlation (P<0.05) between changes in serum ghrelin and leptin levels in healthy controls. Data were analysed statistically by two-group comparison student t test (SigmaStat GmbH, Erkrath) and DISCUSSION expressed as mean±SEM. Pearson’s correlation analysis was used to determine a relationship between the mean This study showed that serum leptin levels were higher levels of serum leptin, ghrelin, cortisol, Hcy, folate, lipids, and ghrelin levels were lower in CTC dogs when compared and thyroid hormones. A P value of <0.05 was considered with the healthy counterparts [26]. Increased serum leptin significant. and decreased ghrelin levels and their correlation with circulating thyroid hormones and lipids in dogs with RESULTS CTC provide further information to understand the pathophysiology of OCD, and to develop new treatment Routine clinical and hematological findings were within strategies for these patients. reference limits in all healthy dogs (data not shown). Dogs In the present study, CTC, one of the most common with CTC had a higher mean body condition score (4.2±0.6; forms of OCD in dogs, was diagnosed as reported P<0.001) than controls (3.2±0.4). earlier [23,25]. Serum leptin concentrations (1.7±0.2 ng/mL), Dogs with CTC had a higher leptin (8.3±0.9 ng/mL vs measured by RIA in healthy dogs, were slightly lower than 1.7±0.2 ng/mL, P<0.001) and lower ghrelin levels (74±7 those of healthy dogs in the previous studies: 2.5±0.1 [13] [26] [31] pg/mL vs 144±41 pg/mL, P<0.05) than those of healthy ng/mL , 2.4±0.1 ng/mL , and 2.3±0.5 ng/mL . controls (Table 1). This difference may be explained by diurnal rhythms of circulating leptin as well as using different measurement Serum cortisol, lipids (cholesterol, phospholipids and methods (RIA or ELISA) and kits (multi-species or canine NEFA) and Hcy levels increased (P<0.05), whereas serum specific leptin) [31]. In this study, no noticeable influence folic acid decreased (P<0.001) in dogs with CTC as compared of age, gender, and breed on serum leptin levels was with controls. There were no statistically significant observed as reported by Ishioka et al.[32]. differences on serum thyroid hormones (except fT3) between the groups studied. Serum fT3 level in dogs with In this study, dogs with CTC had higher leptin (8.3±0.9 CTC was higher (P<0.05) than that of controls (Table 2). ng/mL) and lower ghrelin levels (74±7 pg/mL) than those of healthy controls, indicating a possible association between Serum ghrelin correlated negatively with cholesterol leptin and ghrelin systems and psychogenic disorders 230 Serum Leptin and Ghrelin ... Table 2. Serum levels of leptin and ghreline and their relations with serum lipids, thyroid hormones Parameters T. Cholesterol HDL LDL fT4 Phospholipids Leptin r: 0.600 P<0.05 NS NS r: 0.634 P<0.05 r: 0.643 P<0.05 Ghrelin r: -0.477 P<0.05 r: -0.512 P<0.05 r: - 0.462 P<0.05 NS NS as well as a good inverse correlation between them. The confirm that serum lipid profile might be changed in dogs results of serum leptin in this study showed similarity to suffering from CTC. those of a human study [33], in which serum leptin level was slightly higher (but not statistically significant) in the On the other hand, a significant increase in serum OCD group than in the healthy control group. High body phospholipid and NEFA brings up a new perspective which condition score, observed in dogs with CTC, may enhance may help explain, at least in part, pathophysiological the serum leptin concentration by increasing leptin secretion mechanisms associated with OCDs, such as CTC in dogs. from adipose tissue [24,32,34]. Because phosphatidylcholine, as a primary phospholipid, is found at higher levels in myelin, cell membranes and brain Since active form of ghrelin as compared with total parenchyma [45], it may have a crucial role for development ghrelin is essential in particular for biological [28] and of neuropsychiatric disorders in dogs as in humans [45]. In endocrine activities [35], and thus, is physiologically more addition, excessive serum levels of NEFA, as observed in crucial in terms of OCD [36], active ghrelin measurements the present study, were reported to enhance oxidative were chosen in the present study. Observed serum stress [46] leading to several neuropsychiatric diseases ghrelin level (144±41 pg/mL) in healthy dogs was in good including OCD [47]. Brain tissue has a high percentage of accordance with the levels of 172±17 pg/mL and 117±42 phospholipids that can easily be peroxidized. Recently, pg/mL reported for healthy beagle dogs [37] and humans [38], markers of oxidative stress and free radical induced injury respectively. As compared to healthy controls, serum to the brain tissues in OCD patients were reported, as well. ghrelin levels in dogs with CTC were found lower in this study, whereas Atmaca et al.[39] and Emül et al.[33] reported In this study, of thyroid hormones, only serum fT3 levels a trend of higher ghrelin levels in patients with OCD. These was found to be significantly higher in dogs with CTC than differences of serum ghrelin between the studies might in controls, in accordance with euthyroid syndrome, most have resulted from the presence of depressive disorders probably due to increased tissue metabolic demands in in patients with OCD [33,39]. response to CTC as a non-thyroidal illness in dogs studied. One previous study [48] showed that basal values of thyroid In this study, elevated levels of serum cortisol, as hormones and thyroid stimulating hormone were normal compared to control dogs, were thought to be associated in patients with OCD, and another study [19] reported that with the HPA axis activation in dogs with CTC, in higher rates of panic disorder, OCD, and major depressive concordance with the results in patients with OCD [6]. disorder were observed in thyroid patients than in the In the previous studies, in addition to serum cortisol general population. Aizenberg et al.[49] underlined that elevation, hyperactivity of HPA axis, the main mammalian dysregulation of the hypothalamic-pituitary-thyroid axis in system of stress response [6], was confirmed by increased OCD patients. Our results did not confirm the results arising corticotropin-releasing hormone levels in cerebrospinal from human studies indicating that altered levels of thyroid fluid [40] and increased urinary cortisol levels in patients with hormones might be associated with pathophysiology or OCD [41]. Elevated serum cortisol has been accepted as a maintenance of OCD. physiological marker of stress and behavior abnormalities, particularly for dogs in animal shelter, as well [42]. Since serum Hcy has been considered as a sensitive marker for folate deficiency and they have important Our observations on serum lipid profile confirmed roles in carbon transfer metabolism (methylation) [16,39], and expanded the findings of the previous studies [23,43] in this study serum Hcy and folate levels were evaluated reporting that dogs with CTC had significantly higher total together. Our results of serum Hcy (6.2±0.2 µmol/L) and cholesterol and LDL-cholesterol compared with control folate levels (6.4±0.5 ng/mL) in healthy dogs were in good dogs, by demonstrating the increasing serum phospho- accordance with those of the previous studies in dogs (5.1- lipids and NEFA in dogs studied. The findings of this study 10.9 µmol/L and 4.2-7.5 µg/L, respectively) [50] and humans were very similar to those of a previous study [23]; VLDL- (8.1±2.2 µmol/L and 7.5±1.9 ng/mL, respectively) [16]. In cholesterol and triglyceride levels did not differ significantly this study, serum Hcy levels increased (11±0.8 µmol/L), between the groups. Similar to studies of dogs, elevated and serum folic acid decreased (3.2±0.3 ng/mL) in sick cholesterol [44], LDL- and VLDL-cholesterols and triglyceride dogs, indicating the presence of hyperhomocysteinemia levels were observed in human OCD patients compared and serum folate deficiency in dogs with CTC. 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